Ester hydrohalides of amino acids are often employed as raw materials in the preparation, by a sequence of reactions, of compounds having various uses. Many of them, as for example, L-threonine methyl ester hydrochloride, and L-serine methyl ester hydrochloride, may be used in the preparation of monocyclic .beta.-lactam antibiotics, commonly known as monobactams. L-Phenylalanine methyl ester hydrochloride, may be used in the preparation of aspartame, which is a low-calorie sweetener.
The traditional method for preparing ester hydrochlorides of amino acids is by esterifying the amino acid using alcoholic hydrogen chloride solution. This procedure is cumbersome and lengthy, involving several solvent stripping operations to remove all water and to drive the reaction to completion. Thus, two days are frequently required for a laboratory-sized batch.
A faster known method taking about three hours for a laboratory-sized batch involves the use of thionyl chloride, an expensive raw material, and one that results in the release of sulfur dioxide which presents disposal problems. In many cases, the reaction of thionyl chloride and an amino acid results in a product which, after isolation from the reaction mixture, is a highly viscous liquid which is difficult to crystallize. Although it is not desired to be bound by any theory, it is believed that trace amounts of impurities retard the crystallization.
A third method known for preparing ester hydrochlorides of .alpha.-amino acids involves phosgenation of .alpha.-amino acids to form N-carboxyanhydrides (otherwise known as N-carbonoanhydrides or NCA's) and subsequent reaction of the N-carboxyanhydrides with alcohols. See for example, Iwakura et al, "Benzyl Esters of .alpha.n-Amino Acids", Bulletin of the Chemical Society of Japan, Volume 37, pages 1707-1709 (1964).
It is also known that esters of carboxylic acids may be prepared by reacting the acids with the appropriate chloroformates. See for example, British Patent Specification 730,599 (1955); Matzner et al, "The Chemistry of Chloroformates", Chemical Reviews, Volume 64, pages 654-655 and 677-684 (1964); Domagala, "A Mild, Rapid, and Convenient Esterifiction of .alpha.-Keto Acids", Tetrahedron Letters, Volume 21, pages 4997-5000 (1980); Kim et al, "A New Convenient Method for the Esterification of Carboxylic Acids", Tetrahedron Letters, Volume 24, No. 32, pages 3365-3368 (1983). Chloroformates, however, are not inexpensive materials. The preparation of chloroformates as end products suitable for commerce usually includes one or more purification steps such as a stripping step for the removal of excess phosgene. In some cases the chloroformates are distilled in order to separate them from the carbonates formed as by-products. Each of these additional steps adds to the cost of producing the chloroformates.